窑 Original Article 窑. Jun Ma 1,2 鄢. , Zhe Sheng Wen 1,2, Peng Lin 1,2, Xin Wang 1,2, Fang Yun Xie 1,3. 揖 Abstract 铱 Background and Objective: Methods:

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1 窑 Original Article 窑 Chinese Journal of Cancer The results and prognosis of different treatment modalities for solitary metastatic lung tumor from nasopharyngeal carcinoma: a retrospective study of 5 cases Jun Ma, 鄢, Zhe Sheng Wen,, Peng Lin,, Xin Wang,, Fang Yun Xie, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong 5, P. R. China; Department of Thoracic Oncology, Sun Yat sen University Cancer Center, Guangzhou, Guangdong 5, P. R. China; Department of Radiation Oncology, Sun Yat sen University Cancer Center, Guangzhou, Guangdong 5, P. R. China 揖 Abstract 铱 Background and Objective: Methods: Results: Conclusions: Key words: Nasopharyngeal carcinoma (NPC) is poorly differentiated and thus is highly malignant, which is prone to distal metastasis as compared with other head and neck tumors [,]. A study from Radiation Therapy Oncology Group Correspondence to: Zhe Sheng Wen; Tel: + 4; zheshengwen@yahoo.com.cn 鄢 Now work in Department of Thoracic Surgery, Shanxi Provincial People 爷 s Hospital, Taiyuan, Shanxi, P. R. China. This paper was translated from Chinese into English by Translation and edited by Wei Liu. Received: ; Accepted: Medical (RTOG) showed that carcinomas from the lower laryngeal and nasopharyngeal regions had much higher prevalence of micro metastasis at initial diagnosis []. Thanks to the use of three dimensional conformal radiotherapy and intensitymodulated conformal therapy, the regional control rate of NPC has been markedly improved, and the recurrence rates of NPC and regional lymph nodes have been decreased. As a result, the issue of treatment failure owing to distal metastasis became prominent; about 5% % of the patients with NPC had a treatment failure due to distal metastasis [,4 ]. The lung is the most commonly affected organ, and lung

2 metastasis is one the main causes of treatment failure. Some studies show that some patients with metastasis from NPC may have a good prognosis if comprehensive treatment is used [,]. The patients with lung metastasis from NPC have significantly longer progression free and overall survival than those with other organs involved [5]. The solitary metastatic lung tumor is a distinct metastatic pattern that has particular biological features. It carries better prognosis after treatment. The survival of these patients could be prolonged or the tumor can be cured if treated appropriately. However, there is no consensus on the treatment of such tumor. Chemotherapy, radiotherapy, and operation are the mainstay treatment modalities. Currently, the response rate of solitary metastatic lung tumor from NPC ranges 45% % [ ]. Chemotherapy plays an important role in some of the patients. The development of novel drugs and the use of combination chemotherapy and maintenance chemotherapy in recent years all contribute to the increasing response rate of the disease. However, the overall treatment efficacy is suboptimal. Radiotherapy remains the mainstay treatment of NPC, and is also widely used to treat the metastatic lung tumor from NPC. A study proposed that the local small field radiation was effective for the patients with solitary metastatic lung tumor but without local recurrence []. Some other novel techniques such as directional radiotherapy makes the therapy more accurate and less invasive. Many evidences have proven that operation as a palliative strategy can provide long term survival to the patients []. The widely accepted prognostic factor is the thoroughness of resection. Lung wedge resection and segmental resection are the most commonly used procedures, and have some priorities in the treatment of solitary metastatic lung tumor from NPC. Chemotherapy, radiotherapy, and operation have their merits and limitations in the treatment of solitary metastatic lung tumor from NPC. Chemotherapy alone, radiotherapy or radiochemotherapy, operation or operation plus chemotherapy are usually used. There are few studies comparing the effects of these modalities. The present study reviewed clinical data of 5 patients with metastatic lung tumor from NPC, compared the efficacies of different modalities, and investigated the most appropriate therapeutic modality and the prognostic factors. Clinical data of 5 patients with solitary metastatic lung tumor from NPC treated in Sun Yat sen University Cancer Center between September 4 and September were reviewed. Of them, were initially treated in our center, were diagnosed in other hospitals and then referred to our hospital. The time of initial diagnosis of NPC ranged from April to July. Inclusion criteria: () Patients with pathologically confirmed NPC; () The metastatic lung tumor was determined by chest X ray or chest CT; () Metastasis to other organs were excluded by B mode ultrasound and bone ECT scan; (4) Performance status score during treatment ranged from to ; (5) The therapeutic evaluation of primary lesion and regional lymph nodes was determined to be complete remission (CR) or partial remission (PR); () The metastatic lung tumor was treated in our hospital and the complete clinical data were available. Exclusion criteria: () Those with extra pulmonary metastasis; () Patients with other malignant tumors; () Primary lung cancer was suspected based on the imaging presentation; (4) Needle biopsy or excised specimen of the lung tumor denied NPC derived cancer by immunohistochemical assay; (5) Patients withdrew from the treatment. A total of 5 patients, men and women (.: ), were enrolled. The median age of them was 4 (range: ). Of the 5 patients, 5 (.%) had undifferentiated squamous carcinoma, (.%) had poorly differentiated squamous carcinoma, (.% ) had moderately to highly differentiated squamous carcinoma, round cell carcinoma, and vesicular nucleus cell carcinoma. According to the staging of NPC, (.%) patient had grade I, (.%) grade II, 4 (.4%) grade III, (.%) grade IVa, and (.5%) grade IVb. The diameters of the metastatic lung tumor ranged from. to. cm (mean:.5 cm). Radical radiotherapy was performed for the primary tumor in all patients. The accumulative radiation dose was 4 Gy for primary lesion and 5 4 Gy for regional lymph nodes. Adjunctive chemotherapeutic sensitizations were performed in patients, using cisplatin (DDP) alone or in combination with 5 fluorouracil (5 FU) (PF regimen). Therapeutic efficacy was assessed months after initial treatment, showing cases of CR and cases of PR for primary tumor, and 4 cases of CR and cases of PR for regional lymph nodes. Of the 5 patients confirmed to have solitary metastatic lung tumor, 5 underwent systemic chemotherapy; underwent radiotherapy alone, 4 underwent chemotherapy + radiotherapy; underwent operation alone and 5 underwent operation + adjunctive chemotherapy. Platinum based regimens were used for chemotherapy, including PF, PBF (DDP+BLM+5 FU), and GP (GEM+DDP) regimens. Twenty two patients underwent local small field radiation (total dose, 5 Gy), underwent total lung radiation ( 4 Gy) + local small field ; Vol. Issue

3 complementary radiation (5 Gy). Twenty six patients underwent single operation, underwent a second operation due to recurrent lung tumor, and underwent a third operation; cases of lung wedge resection and lung segmental resection, and cases of lobectomy were performed. Eight cases of lymph node dissection or sampling were performed, and the postoperative pathology showed cases of mediastinal lymph node metastases and 5 cases free of metastasis. tests were performed if the variance was homogeneous, otherwise, the Tamhane 爷 s T test was performed. OS rates were calculated using the Kaplan Meier method and compared by the log rank test. Statistical significance was defined when <.5 by the two tailed test. Multivariate analysis was performed using Cox proportional hazard regression model. According to the treatment modalities, the patients were divided into chemotherapy alone group, radiotherapy +/ chemotherapy group, and operation +/ chemotherapy group. The short term and long term efficacy of different treatment modalities were evaluated. The short term efficacy, based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria, were assessed as CR, PR, stable disease (SD), progressive disease (PD), and no assessment (NA); CR and PR were regarded as treatment responses. The efficacy was assessed at weeks after chemotherapy, months after radiotherapy, and month after operation. The patients were followed up till January,. The long term efficacy was evaluated according to the progression free survival (PFS) and overall survival (OS). OS was calculated from the first day at the completion of treatment to death or to the end of follow up, and PFS was calculated from the completion of treatment to the disease progression (newly occurred metastatic lesion, recurrence or expansion of the primary lesion). Disease free interval (DFI) was calculated from the completion of initial treatment to the time when the lung lesion was identified. The hilar/mediastinal lymph node involvement was defined when the imaging showed lymph nodes > cm in diameter or the dissected specimen was pathologically positive. Univariate and multivariate analyses for patients 爷 survival were performed by incorporating factors such as gender, age (< 45, 逸 45), pathologic type, stage of NPC, initial use of adjunctive chemotherapy, treatment evaluation of NPC, DFI, the size of metastatic lung tumor, the involvement of hilar or mediastinal lymph nodes after lung metastasis, treatment of metastatic lung tumor, recurrence and distal metastasis. No death or severe complications were reported during treatment. All 5 patients were followed up with complete data available (Table ). The median follow up was. months (range: months). The median DFI was. months ( months). Short term efficacy was assessable in patients (Table ); were not assessed because they hadn 爷 t undergone chest CT scan in due time. The local control rate was significantly lower in chemotherapy group than radiotherapy +/ chemotherapy group and operation +/ chemotherapy group (5.% vs..% and.4%, <.). The OS rates, PFS and OS are shown in Table. Operation +/ chemotherapy prolonged the PFS and OS, and radiotherapy +/ chemotherapy also improved survival rate. Both modalities were superior to chemotherapy ( <.) (Table 4). Figures and demonstrate the PFS and OS curves of the patients under different treatment modalities. Cox proportional hazard regression analyses showed that recurrent distal metastasis or local recurrence affected the prognosis of solitary metastatic lung tumor from NPC (OR =., 5% CI =..4, =.). Fifty one (4.%) patients had recurrent distal metastasis: (.%) had lung metastasis, (.% ) had bone metastasis, (.% ) had liver metastasis, (.% ) had other sites involved, and (.5%) had multiple metastases. After treatment for metastatic lung tumor from NPC, (.% ) patients had nasopharyngeal recurrence, (.% ) had regional lymph node recurrence. Moreover, the size of metastatic tumor, status of hilar/mediastinal lymph nodes, T stage of NPC, and treatment modality all related with the survival (Table 5). Statistical analysis was performed using SPSS. package. The relationship between different treatment modalities and clinicopathologic factors was analyzed using the Chi square test. Data of short term efficacy were tested for homogeneity of variance. One Way ANOVA and LSD t NPC is common in China. The lungs are the most common site of metastasis, and no consensus exists for its treatment. The present study retrospectively reviewed clinical data of the patients with solitary metastatic lung tumor from NPC, and compared the short and long term

4 Characteristic Age < 45 years 逸 45 years Gender Male Female Histologic differentiation Undifferentiated Poor Moderate or well Pathologic TNM stage (NPC 爷 )* I and II III IV T classification (NPC 爷 ) T T T T4 N classification (NPC 爷 ) N N N N Adjuvant chemotherapy for NPC Yes No Nasopharyngeal evaluation Complete remission Partial remission Regional lymph node evaluation Complete remission Partial remission Disease 鄄 free interval < months - months 逸 months Size of pulmonary metastasis < cm 逸 cm Positive Negative Cases (n) Pulmonary hilar and/or mediastinal lymph node metastasis Recurrent distant metastases or/and relapse of NPC Yes 5 No 4 Chemotherapy (n) Radiotherapy +/- chemotherapy (n) 5 4 Operation +/- chemotherapy (n) P 鄢 NPC 爷 stage, Chinese staging system for nasopharyngeal carcinoma. efficacies of chemotherapy, radiotherapy +/ chemotherapy, and operation +/ chemotherapy. Our results showed that operation +/ chemotherapy was superior to the other two modalities ( <.), which improved the local control rate, prolonged the PFS and OS. Moreover, radiotherapy +/ chemotherapy was also superior to chemotherapy alone ( <.). Currently, operation is rarely used to treat metastatic lung tumor from NPC. Cheng. [] reported that the patients treated by surgical resection of solitary metastatic ; Vol. Issue

5 Treatment of lung metastasis Chemotherapy Radiotherapy +/- chemotherapy Operation +/- chemotherapy Cases (n) 5 5 CR PR SD Local control* PD NA CR+PR (%) 5.. a.4 a,b *Local control was evaluated by RECIST criteria.: CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease; NA, not assessable. a P <., vs. chemotherapy; b P<., vs. radiotherapy +/- chemotherapy. Group Chemotherapy Radiotherapy +/- chemotherapy Operation +/- chemotherapy Total 鄄 year Survival rate (%) 鄄 year 鄄 year Mean PFS (months) Max 5 5 OS (months) Mean Max lung tumor plus adjunctive chemotherapy had higher year survival rate than the 5 patients treated by chemotherapy alone (.% vs. 4.%, <.). These results are consistent with ours. For the patients with solitary metastatic lung tumor from NPC, operation is recommended if there is no contraindication. Operation shows some priorities. First, the excised specimen is sent for immunohistochemical assay and compared with the primary lesions, which can help to exclude the potential primary lung cancer that has different treatment modalities [,5]. The patients who undergo chemotherapy and/or radiotherapy are determined to have metastatic lung tumor based on medical history, imaging, and Epstein Barr virus (EBV) related antibody titers, and thus risk the likelihood of misdiagnosis. Second, surgical resection of the metastatic lung tumor features in completeness of resection, minimal invasiveness, rapid recovery, and short treatment course. In contrast, radiotherapy, despite of its high accuracy of localization, may be uncertain in the therapeutic effect. The short term efficacy of operation is optimal. Third, in addition to the tumor resection, the remaining pulmonary lobes can be examined by palpation during operation to identify some potential nodules that are not demonstrated in imaging. Forth, suspected lymph nodes can be dissected during operation to evaluate the lymph node status. The patients with lymph node metastasis should undergo lymph node dissection and postoperative comprehensive treatment. The patients who have unresectable tumors, contraindicate to operation, or are unwilling to receive operation could be recommended to have radiotherapy +/ chemotherapy. The metastatic lung tumor from NPC is sensitive to radiotherapy. Yi. [] treated patients with metastatic lung tumor from NPC by different modalities, and found that the effective rate of radiotherapy was.%, and that the radiotherapy +/ chemotherapy ( cases) was more effective than chemotherapy alone ( cases) ( =.). In our study, 5 patients underwent radiotherapy +/ chemotherapy, and the, and 5 year survival rates were.%, 5.% and 4.%, respectively, the median survival time was 4. months. The effective rate of radiotherapy was.%, and its short term efficacy and its benefit to the PFS and OS were superior to chemotherapy alone. X ray stereotactic radiotherapy (SRT) is developed in recent years and is a treatment option of metastatic lung tumor because its radiation energy can be accurately targeted to the lesion with little injury to the neighboring normal tissues, and it is not restricted by the sensitivity of the tumor tissue. In addition, the use of SRT is not restricted by the patients 爷 general condition. It is less invasive with little injury to the body, and is suitable to patients with surgical contraindications. Wu. [] observed cases of metastatic lung tumor treated, including from NPC, with SRT. The short term efficacy was.%, and the year OS rate of the patients with solitary metastatic lung tumor was 5.%. However, the number of patients with metastatic lung tumor from NPC treated with SRT is small, and most of them have small tumors. The long term efficacy mandates further investigations. Both operation and radiotherapy are local treatments, and do not affect the biological behaviors and metastatic nature of the tumor. For advanced NPC, the treatment should target its biological behaviors, that is, comprehensive modalities, including chemotherapy, biological target therapy, and genotherapy, can be used to eliminate the micro metastatic lesions, thereby prevent the spread of the tumor. Currently, chemotherapy is the most widely used

6 Characteristic Age < 45 years 逸 45 years Gender Male Female Histologic differentiation Undifferentiated Poor Moderate or well Pathologic TNM stage (NPC 爷 ) I and II III IV T classification (NPC 爷 ) T T T T4 N classification (NPC 爷 ) N N N N Adjuvant chemotherapy for NPC Yes No Nasopharyngeal evaluation Complete remission Partial remission Regional lymph node evaluation Complete remission Partial remission Disease 鄄 free interval < months - months 逸 months Size of lung metastasis < cm 逸 cm Pulmonary hilar and/or mediastinal lymph node metastasis Positive Negative Treatment of lung metastasis Chemotherapy Radiotherapy +/- chemotherapy Operation +/- chemotherapy Recurrent distant metastases or/and relapse of NPC Yes No Cases (n) Death cases [n(%)] (.) 4 (.5) (4.) (.) (5.) 5 (.) (5.) (.) (.4) (5.5) (5.) (5.) 5 (.) (4.4) (.) (5.) (5.) (.4) 4 (.) (4.4) 4 (4.) 5 (.) (5.5) (.) (.) (4.) (.) 54 (5.) 5 (5.) (4.) 5 (.) 4 (.) (4.) 5 (5.) 55 (4.) 4 (5.) 字 P treatment of this disease. Studies show that active chemotherapy can prolong the disease free survival in a fraction of NPC patients with distal metastasis [,]. Most patients with metastatic lung tumor undergo chemotherapy ; Vol. Issue

7 Simplex Chemotherapy Radiotherapy +/- Chemotherapy Operation +/- Chemotherapy Simplex Chemotherapy censored Radiotherapy +/- Chemotherapy 鄄 censored Operation +/- Chemotherapy 鄄 censored P 约. (n = patients) 4 (n = 5 patients) (n = 5 patients) 5 5 Time (months) Figure Progression 鄄 free survival (PFS) curves of patients with solitary lung metastasis from nasopharyngeal carcinoma (NPC) treated by different treatment modalities Simplex Chemotherapy Radiotherapy +/- Chemotherapy Operation +/- Chemotherapy Simplex Chemotherapy censored Radiotherapy +/- Chemotherapy 鄄 censored Operation +/- Chemotherapy 鄄 censored P 约. 4 (n = patients) (n = 5 patients) (n = 5 patients) 5 5 Time (months) Figure Overall survival (OS) curve of patients with solitary lung metastasis from NPC treated by different treatment modalities

8 Item Distant metastases or relapse of NPC Different treatment of lung metastasis Hilar and/or mediastinal lymph node metastasis Size of lung metastasis T stage (NPC 爷 ) SE OR % CI for Exp(B) P CI, confidence interval. because they have multiple metastases in the lungs or have other organs involved, and those initially have solitary metastatic lung tumor carry a high risk of recurrence. Among our patients with solitary metastatic lung tumor from NPC, 4.% had recurrent metastasis after treatment, mostly in the lungs, bone, and liver. Thus, chemotherapy as a systemic treatment is very important. Chemotherapy has the synergistic effect with operation and radiotherapy by acting on different targets. Moreover, chemotherapy can arrest the tumor cells in the radiotherapy sensitive phase, thereby improving the local control rate and OS of patients treated by radiotherapy. However, in our study, the efficacy of chemotherapy alone was worse than the other two modalities. It is probably that the metastatic lung tumors from NPC are poorly differentiated or undifferentiated squamous carcinoma, and thus is moderately sensitive to chemotherapy. Leong. [] has demonstrated that maintenance regimen with 5 FU and folinic acid following the triple regimen of gemcitabine, paclitaxel and carboplatin had certain effect on distal metastasis from NPC. To further improve the efficacy of chemotherapy on metastatic lung tumor from NPC, novel drugs or regimens with a high sensitivity are urgently needed. In addition, the Cox proportional hazard regression model revealed that the recurrence of distal metastasis and primary tumor are major prognostic factors (OR =., =.). The size of metastatic tumor, status of hilar/mediastinal lymph nodes, T stage of NPC, and the therapeutic modality were independent prognostic factors of the metastatic lung tumor from NPC. For patients with high risk factors, such as advanced T stage, a diameter of the tumor of 逸 cm, and positive mediastinal lymph nodes, adjunctive chemotherapy is recommended, which may be beneficial to the prognosis. Conclusively, operation +/ chemotherapy and radiotherapy +/ chemotherapy are effective for the solitary metastatic lung tumor from NPC in improving the local control rate, prolonging PFS and OS. Operation based comprehensive therapy is recommended for the patients with solitary metastatic lung tumor from NPC but without other organs involved or surgical contraindications. Otherwise, radiotherapy +/ chemotherapy is the option for those with unresectable tumor, contraindications to operation, or are reluctant to have operation. Adjunctive 4 systemic chemotherapy is indicated for patients with advanced T stage, diameters of the metastatic lung tumor of 逸 cm, or positive hilar/mediastinal lymph nodes. Due to the retrospective nature of the present study, the results need to be confirmed by multicenter, randomized, controlled trials. Metastatic lung tumor from NPC is an advanced disease. The aim of future studies is to develop an individualized modality for each patient, thereby relieving clinical symptoms, improving the quality of life and prolonging patients 爷 survival. 咱 暂 咱 暂 咱 暂 咱 4 暂 咱 5 暂 咱 暂 咱 暂 咱 暂 咱 暂 Lee N, Xia P, Quivey JM, et al. Intensity 鄄 Modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the USCF experience [J]. Int J Radiat Oncol Biol Phys,, 5 (): -. Ma J, Mai HQ, Mo HY, et al. Patterns of treatment failure after primary radiotherapy in patients with nasopharyngeal carcinoma [J]. Ai Zheng,,():-. [in Chinese] Leibel SA, Scott CB, Mohiuddin M, et al. The effect of local 鄄 regional control on distant metastatic dissemination in carcinoma of the head and neck: results of an analysis from the RTOG head and neck database [J]. Int J Radiat Oncol Biol Phys,, (): Cheng SH, Yen KL, Jian JJ, et al. Examining prognostic factors and patterns of failure in nasopharyngeal carcinoma following concomitant radiotherapy and chemotherapy: impact on future clinical trials [J]. Int J Radiat Oncol Biol Phys,, 5 (): -. Hui EP, Leung SF, Au JS, et al. Lung metastasis alone in nasopharyngeal carcinoma: a relatively favorable prognostic group. A study by the Hong Kong Nasopharyngeal Carcinoma Study Group [J]. Cancer, 4, ():-. Lee AW, Sze WM, Au JS, et al. Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience [J]. Int J Radiat Oncol Biol Phys, 5, (4):-. Chan AT, Teo PM, Leung TW, et al. The role of chemotherapy in the management of nasopharyngeal carcinoma [J]. Cancer,, (): -. Fandi A, Bachouchi M, Azli N, et al. Long 鄄 term disease 鄄 free survivors in metastatic undifferentiated carcinoma of nasopharyngeal type [J]. J Clin Oncol,, (): 4-. Yi JL, Xu GZ, Gao L, et al. The results and prognosis of different treatment for lung metastasis from nasopharyngeal carcinoma: analysis of patients [J]. Chin J Radiat Oncol, 5 ():- 5. [in Chinese] ; Vol. Issue

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